The long-term goal of this group is to establish a multi-investigator, interdisciplinary research program with focus on disorders of the developing nervous system. Such disorders will include mental retardation syndromes, learning and behavioral disorders of childhood onset and adult onset psychiatric disorders for which a developmental basis is strongly suggested by current research literature. The current proposal is based on previous and preliminary studies in mouse by the activity leader and collaborators that have shown behavioral and structural sexual dimorphism in mice and suggested the susceptibility of this dimorphism to developmental alterations in afferent cortical modulatory systems. The focus of the present proposal is to study the developmental relationships between the neuromodulatory neurotransmitters acetylcholine [ACh], norepinephrine [NE], dopamine [DA], and serotonin [5- HT], sex hormones and cortical morphogenesis in this mouse model. The hypothesis we aim to test is that structural sex differences in mouse cerebral cortex and accompanying differences in behavior result from altered neuromodulatory regulation of cortical ontogeny. To test this hypothesis we will 1) assess alterations in cortical cytoarchitecture of male and female mice resulting from selective block of specific neuromodulator systems in development; this will entail the development of selective inhibitors by Dr. Hajjii, Dept. of chemistry; 2) determine whether there are sex differences in neuromodulator level or time of fiber ingrowth during ontogeny of cerebral cortex; (3) test how experimentally altered hormonal levels in development affect the ontogeny of the neuromodulator systems in male versus female mice; 4) begin to study molecular mechanisms through which sex hormones and neuromodulators impact morphogenesis and subsequent behavior; 5) begin a pilot study to assess whether adversive stress and environmental toxins affect the interactions between sex hormones and neuromodulatory chemistry, resulting in altered behavioral function. Since many CNS disorders with developmental onset affect male and females differentially, elucidating the ontogeny of sexual dimorphism in cerebral cortex will help us to better understand the etiology of such disorders. Furthermore, the proposed studies are designed to enable the Neurodisorder/Neurodevelopment group to increase the research capabilities, infrastructure and support for existing faculty as well as expand the research scope by adding additional faculty expertise and by developing interdisciplinary projects with investigators in other disciplines and institutions.